Medical fluid, a method of treatment and use of the fluid

ABSTRACT

A medical fluid for a harvested organ, tissue or parts thereof, for evaluation and/or preservation. The fluid includes cocaine or a stimulating analogue thereof; nor-adrenalin; and/or adrenaline. In addition, the fluid includes an oncotic agent, such as dextran; hormones, such as thyroxin; triiodotyronine; cortisone, insulin; and electrolytes and optionally nutrients in substantially physiological concentrations in a physiologically acceptable medium. In addition, the medical fluid further includes albumin in a concentration not exceeding 5.0%, and an oxygen carrier, such as erythrocytes. Further components may be dopamine; hydrocortisone; methylprednisolone; and a vasopressor agent, such as desmopressin. The cocaine; adrenalin; and noradrenaline are present in concentrations of each about 0.010 μM to 0.100 μM, for example in a ratio of 1:1:1.

FIELD OF INVENTION

The present invention relates to a method of handling an organ afterharvesting, including a medical fluid and use of said fluid.

BACKGROUND OF THE INVENTION

It is well known that there is a great shortage of donor organs, whichmay be used for transplantation.

After harvesting, the organs should be examined and evaluated forviability to be used for transplantation purpose. The evaluation may beperformed at a physiological temperature of about 37° C., such asbetween 30° C. and 40° C., or alternatively at a lower temperature.During the evaluation, the organs may be perfused by and/or surroundedby an evaluation fluid similar to blood.

Normally, the organs cannot be transplanted immediately, but a recipientshould be found, which may take some time. Moreover, the organ to betransplanted should be transported to the recipient or the recipient betransported to the organ. Thus, the organs may be preserved for somehours or days, often at hypothermal conditions. During preservation, theorgans may be perfused by and/or surrounded by a preservation fluid.

There are several previously known evaluation fluids and preservationfluids. Such medical fluids involve compromises between cost andperformance.

An evaluation fluid may operate at a physiological temperature of about37° C. and provide support for metabolism of the organ, at least to acertain degree. Such a fluid may be whole blood or a synthetic fluidoperating similar to blood, or a combination.

A preservation fluid may be optimized for operation at low temperature,during which the metabolism of the organ is low.

There is a need for a medical fluid, which is more versatile than thosepresently used, and which is suitable for evaluation and preservation oforgans after harvesting and before transplantation.

WO2010077200A1 and WO2010077201A1 disclose fluids which are used forsupporting body functions in a brain-dead body. The contents of thesepatent applications are incorporated in the present specification byreference.

DISCLOSURE OF THE INVENTION

Accordingly, an object of the present invention is to mitigate,alleviate or eliminate one or more of the above-identified deficienciesand disadvantages singly or in any combination.

In an aspect, there is provided a medical fluid for a harvested organ,tissue or parts thereof, for evaluation and/or preservation, comprising:cocaine or a stimulating analogue thereof; adrenalin and/ornoradrenalin; an oncotic agent; hormones; and electrolytes andoptionally nutrients in substantially physiological concentrations in aphysiologically acceptable medium. Cocaine, noradrenaline, if present,and adrenaline, if present, may be in concentrations of about 0.010 μMto 0.100 μM. The oncotic agent may be albumin or dextran or acombination thereof. The hormones may be any one of thyroxin;triiodotyronine; or cortisone or a combination thereof. The fluid mayfurther comprise an oxygen carrier, such as erythrocytes. The fluid mayfurther comprise at least one of glucose; insulin; dopamine;hydrocortisone; methylprednisolone; and a vasopressor agent, such asdesmopressin. The cocaine or a stimulating analogue thereof; adrenalin;and noradrenaline may be present in concentration ratios of 1:1:1.

In another aspect, there is provided a method for treatment of aharvested organ for evaluation and/or preservation, comprising:circulating a first fluid in the vascular system of the organ, andoptionally partly or completely immersing said organ in a second fluid;said first fluid comprising cocaine or a stimulating analogue thereof;adrenalin and/or noradrenalin; an oncotic agent; hormones; andelectrolytes and optionally nutrients in substantially physiologicalconcentrations in a physiologically acceptable medium.

In a further aspect, there is provided a use of a fluid for a harvestedorgan, tissue or part thereof for evaluation and/or preservation,wherein the fluid comprises the components mentioned above.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects, features and advantages of the invention will becomeapparent from the following detailed description of embodiments of theinvention with reference to the drawings, in which FIG. 1 is a schematicview of a nerve terminal.

DETAILED DESCRIPTION OF EMBODIMENTS

Below, several embodiments of the invention will be described. Theseembodiments are described in illustrating purpose in order to enable askilled person to carry out the invention and to disclose the best mode.However, such embodiments do not limit the scope of the invention.Moreover, certain combinations of features are shown and discussed.However, other combinations of the different features are possiblewithin the scope of the invention.

DEFINITIONS

In the context of the present description and embodiments the followingdefinitions apply: The term “cocaine analogue” is intended to mean ananalogue, which acts in the same or a similar way as cocaine inpreserving organs after harvesting of the organs. The term“Pharmaceutically acceptable” means a non-toxic material that does notdecrease the effectiveness of the biological activity of the activeingredients. The term “physiologically acceptable solution” means asolution that does not interfere substantially with the fluids in thebody. Such pharmaceutically acceptable buffers, carriers or excipientsare well-known in the art, see for example Remington's PharmaceuticalSciences, 18th edition, A.R. Gennaro, Ed., Mack Publishing Company(1990) and handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe,Ed., Pharmaceutical Press (2000).

An object of the below described embodiments is to improve the outcomeof organs harvested from a donor and transplanted to a recipient. Ahypothesis is that the outcome of organs after transplantation may beimproved by use of a fluid comprising adrenaline (epinephrine) and/ornor-adrenaline (nor-epinephrine). Thus, an understanding of the role ofthese catecholamines in the living human and/or mammalian body is ofinterest.

Adrenaline and noradrenaline are neurotransmitters which influence uponalfa- and beta-receptors, and have numerous actions in the body.

Adrenaline and nor-adrenaline may as well be regarded as hormonesbecause they are secreted by the adrenal medulla into the blood streamin the living (mammal) body. Normal human secretion in the adrenalmedulla of adrenaline may be 0.2 μg per kg and min and of nor-adrenaline0.05 μg per kg and min. Normal plasma adrenaline concentration is about0.05 to 0.5 mg per liter in a living human body. In certain conditions,the plasma adrenaline concentrations may be increased more than tentimes.

In addition, noradrenaline is produced in the pre-synaptic adrenergicnerve terminal from tyrosine, which is an amino acid present all overthe body in large quantities.

FIG. 1 is a schematic and simplified view showing a nerve terminal ofthe sympathetic nerve system. The nerve terminal ends in a presynapticadrenergic varicosity 11 having a cell membrane 12. A postsynapticeffector cell membrane 14 is positioned a short distance from the cellmembrane 12. The distance is called the synaptic cleft and may be about20 nm in a chemical synapse.

Tyrosine is transported into the varicosity 11 via a transporter 15 andinto the cytoplasm, wherein the tyrosine is converted to DOPA under theinfluence of an enzyme; Tyrosine Hydroxylase (TH). This step isconsidered to be the rate-limiting step in the synthesis ofnor-adrenaline and adrenaline.

DOPA is transformed to dopamine in the cytoplasm under the influence ofan enzyme; Aromatic L-amino acid decarboxylase (AAADC).

Dopamine is taken up into vesicles 16 via an active transporter 17called VMAT-2 (Vesicular Monoamine Transporter), which is relativelynon-specific and can transport different catecholamines, such asnor-adrenaline and dopamine, and other substances. Only about 50% of thedopamine produced is normally transported into the vesicles 16; the restis metabolized in the cell by an enzyme called MAO (Monoamine Oxidase),see further below. There are a great number of vesicles in the nerveterminal.

Inside the vesicle, there is an enzyme; Dopamine-β-hydroxylase (DβH),which converts the dopamine entering the vesicle into nor-adrenaline(NA). In addition, any nor-adrenaline present inside the varicosity 11is transported into the vesicle 16 by the same transporter 17, VMAT-2.In this way, nor-adrenaline is reused. A portion of the nor-adrenalineinside the varicosity does not enter the vesicle 16 but is metabolizedby the enzyme MAO. Thus, there is a competition between the enzyme MAOand the active transporter 17 VMAT-2, both with regard to dopamine andnor-adrenaline.

The concentration of nor-adrenaline inside the vesicle is very high. Aconcentration in the range of 1 mole/liter has been reported.

At depolarization of the nerve cell membrane at the arrival of astimulation signal, several voltage dependent calcium ion channels 18allow the passage of calcium ions through the varicosity membrane 12.Elevated levels of calcium ions promote the fusion of vesicular membranewith the membrane of the varicosity with subsequent exocytosis ofnor-adrenaline, NA. The fusion process involves the interaction ofspecialized proteins associated with the vesicular membrane (VAMPs,vesicle-associated membrane proteins) and the membrane of the varicosity(SNAPs, synaptiosome-associated proteins). When the vesicle emits itscontent into the synaptic cleft, the nor-adrenaline passes into thesynaptic cleft and may interact with alfa- and beta-receptors present atthe effector cell membrane, as shown by arrows in FIG. 1. Since theconcentration of nor-adrenaline in the vesicle is extremely high andbecause the concentration of nor-adrenaline in the synaptic cleftnormally is very low, and because the distance across the synaptic cleftis very small, some 20 nm, the nor-adrenaline will more or less explodewhen released from the vesicle due to the high concentration gradientand rapidly reaches the receptors at the effector cell membrane. Theentire process comprising receipt of a depolarization voltage, inflow ofcalcium and exocytosis of nor-adrenaline takes often less than one tenthof a second.

The released nor-adrenaline may also interact with presynaptic receptorsof alfa-2-type and beta-type. The alfa-2-receptor may influence directlyon the vesicle and diminish the release of nor-adrenaline. Thebeta-receptor may facilitate the release of nor-adrenaline. Themechanism is not clearly understood for such direct influence of therelease of the nor-adrenaline.

After some time, nor-adrenaline attached to the receptors is releasedfrom the receptors in the synaptic cleft. The nor-adrenaline present inthe synaptic cleft is transported into the adrenal varicosity by anactive transporter 19, called NET (nor-epinephrine transporter,nor-epinephrine=nor-adrenaline). This transporter has a high affinityfor nor-adrenaline. NET removes free nor-adrenaline from the synapticcleft, often within 0.1 seconds. However, a small portion of the freenor-adrenaline in the synaptic cleft passes out to the surroundinginterstitial fluid and subsequently to the vascular blood circulation.Circulating nor-adrenaline is rapidly metabolized in the liver, normallywithin a few minutes.

Thus, most of the nor-adrenaline released during exocytosis is reused. Aportion is lost to the circulation and a portion is lost inside theadrenergic varicosity due to metabolization by MAO before entering thevesicle 16. Such lost nor-adrenaline is replaced by newly producednor-adrenaline from tyrosine as explained above.

There is a negative feed-back regulation of the synthesis ofnor-adrenaline from tyrosine. Thus, a high concentration ofnor-adrenaline at the presynaptic alfa-2-receptors seems to decrease theproduction of nor-adrenaline, probably via interference with therate-limiting enzyme TH.

The distance from the synaptic cleft to the blood circulation may be inthe range of about 0.1 μm to several millimeters and is thus larger thanthe synaptic cleft. Thus, it takes long time for nor-adrenaline todiffuse from the synaptic cleft to the blood circulation and vice versa.Consequently, the concentration of circulating nor-adrenaline in theblood of a living human body is normally low. In addition, it takes ahigh concentration in the blood in order for some nor-adrenaline todiffuse to the synaptic cleft and influence upon the receptors of theeffector cell.

There are indications in the literature that a nor-adrenaline plasmaconcentration in the living body of about 1.5 mg per liter (about 9 μM)is required in order to observe a physiological change. Thecorresponding plasma concentration for adrenaline is about 0.05 mg perliter (0.3 μM).

Adrenaline is produced from nor-adrenaline by an extra enzymaticallydriven step in the adrenal medulla. The enzyme is calledphenylethanolamine N-methyltransferase (PNMT) and convertsnor-adrenaline to adrenaline. This enzyme is present essentially only inthe adrenal medulla. The adrenal medulla comprises nerve terminalssimilar to the adrenergic varicosity shown in FIG. 1 but lacks apostsynaptic portion. Instead, the exocytosis takes place directly intothe blood stream. Normally, the adrenal medulla excretes about 80%adrenaline and 20% nor-adrenaline into the blood.

The above description is valid for a living mammal body, such as thehuman body.

Circulating adrenaline and noradrenaline are metabolized by the liverand have a half-life of approximately a few minutes when circulating inblood. Other metabolization paths are also known.

It is reported in the literature that administration of nor-adrenalineto the vascular system has been associated with myocardial damage andinitial nonfunctioning after cardiac transplantation. It is hypothesizedthat the nor-adrenaline may cause myocardial ischemia and/ordesensitization of the beta-adrenergic signaling pathway. Administrationof nor-adrenaline may further desensitize the myocardial beta-adrenergicsignaling. The recovery potential of BAR remains unknown, but may havean impact on organ function.

When an organ has been harvested, the organ may be evaluated forsuitability for transplantation. Such evaluation may involveadministration of a medical fluid to the vascular system of the organduring physiological temperature.

If the organ is the heart, the evaluation may involve measurement of theorgans ability to pump fluid. If the organ is the lungs, the organsability to add oxygen and remove carbon dioxide may be measured. Forother organs, the organs ability to operate as required may be assessed.

A medical fluid used for such purpose may be for example Steen Solutiondisclosed in WO 2002/35929 A1, the contents of which are incorporated inthe present specification by reference. Such medical fluid may comprisesalts and nutrients as well as serum albumin and for example dextrancompounds. In addition, erythrocytes may be added for oxygen supply.Thus, the evaluation fluid is able to support oxygenation and nutritionof the cells.

However, although the evaluation fluid comprises oncotic agents, thereis a risk that the organ forms edema.

A hypothesis is that the vascular system of the organ may have lost itsvasotonus. The reason may be that the nerves are at least partlydenervated and no activation signals are received by the nerveterminals. Consequently, the nerve terminals do not emit nor-adrenalineinto the synaptic cleft.

In addition, the adrenal medulla is no longer connected to the organ.Thus, the organ does not receive adrenaline and noradrenaline. Depletionof nor-adrenaline may results for example in that the vascular system ofthe organ loses its vasotonus, and the vascular bed becomesvasodilatated. The endothelial cells may be unable to resist outflow offluid into the interstitial volume, resulting in edema formation and/ororgan swelling. Depletion of adrenaline may result in down-regulation ofbeta adrenergic cardiac receptors (BAR), i.e. a reduction of BARdensity, which potentially may result in poor transplant outcome.

Thus, according to an embodiment, adrenaline may be included in themedical fluid in concentrations lower or similar to those normallyencountered in the blood. The added adrenaline interacts withbeta-receptors to promote for example cardiac output. Adrenaline hasnumerous other actions in the organs as is well known to the skilledperson.

According to another embodiment, nor-adrenaline may be included in themedical fluid in concentrations sufficient to cause diffusion from theblood to the synaptic cleft and to the receptors present therein, forexample alfa-receptors, in order to interact with for examplealfa-receptors to cause vasoconstriction for at least partly maintainingvasotonus. Nor-adrenaline has numerous other actions in the organs as iswell known to the skilled person.

However, nor-adrenaline is normally produced and normally acts at sitesdifferent from the vascular system. This fact may be a cause todifferent results when adding nor-adrenaline to fluids entered into thevascular system, as reported in the literature.

One mechanism which may decrease the action of the nor-adrenalinecirculating in the vascular system and diffusing to the synaptic cleft,may be the fact that any nor-adrenaline reaching the synaptic cleft willbe rapidly taken up by the NET transporter and be entered into thepresynaptic nerve terminal. Thus, the NET transporter will compete withthe activation of the effector cell receptors and decrease the action ofthe nor-adrenaline present in the vascular system and diffusing to thesynaptic cleft. When added to the vascular system, nor-adrenaline tendsto be absorbed or soaked up by the nerve terminals.

The inventor has found that the addition of cocaine together withnor-adrenaline would permit the use of lower levels of nor-adrenaline inthe vascular system than normally found in the living body, and stillobtain the desired effects of at least partly maintained vasotonus. Onehypothesis may be that the cocaine acts as NET inhibitor, which ispreviously known. By blocking the reuptake of the nor-adrenaline fromthe synaptic cleft, the NET transporter will no longer compete with thealfa-receptor and the nor-adrenaline diffusing from the vascular systemto the synaptic cleft may cause the desired action and at least partlymaintain vasotonus. Other explanations may be relevant in combination.

By the use of lower than normal concentration of nor-adrenaline, anynegative effect of high concentration of nor-adrenaline in the vascularsystem can be counteracted.

In addition, it has been found that cocaine may interact with adrenalinefor preserving the BAR receptors, and possibly prevent down-regulationof BAR receptors and may have other beneficial effects.

In a further embodiment, the medical fluid may comprise both adrenalineand nor-adrenaline and in addition cocaine.

In one embodiment, cocaine (benzoylmethyl ecgonine) has been used.Cocaine acts as a NET inhibitor of nor-adrenaline and dopamine.

Cocaine may also or alternatively act via further mechanisms not knownor appreciated today, and may have a beneficial effect for preservingorgans after harvesting.

Cocaine analogues may operate in the same way. Analogues may be anyanalogue as defined above. It is believed that it is the stimulanteffect of cocaine that is active. Thus, cocaine analogues mean cocaineanalogues with stimulating effect.

Cocaine-analogues with both stimulant & local anesthetic effects are forexample: Dimethocaine or larocaine (DMC)((3-diethylamino-2,2-dimethylpropyl)-4-aminobenzoate); and3-(p-Fluorobenzoyl)tropane((1R,5S)-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-fluorobenzoate).

Cocaine-analogues for stimulant effects with local anesthetic effectsremoved are for example: β-CIT (methyl(1R,2S,3S,5S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate);β-CPPIT (3β-(4′-Chlorophenyl)-2β-(3′-phenylisoxazol-5′-yl)tropane);FE-β-CPPIT(N-(2′-Fluoroethyl)-3β-(4′-chlorophenyl)-2β-(3′-phenylisoxazol-5′-yl)nortropane);FP-β-CPPIT(N-(3′-Fluoropropyl)-3β-(4′-chlorophenyl)-2β-(3′-phenylisoxazol-5′-yl)nortropane);Altropane (methyl(1R,2S,3S,5S)-3-(4-fluorophenyl)-8-[(E)-3-iodoprop-2-enyl]-8-azabicyclo[3.2.1]octane-2-carboxylate);Brasofensine((E)-1-[(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-yl]-N-methoxymethanimine);CFT (methyl(1R,2S,3S,5S)-3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate);Dichloropane (methyl(1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate);Difluoropine (methyl(1S,2S,3S,5R)-3-[bis(4-fluorophenyl)methoxy]-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate);Ioflupane (¹²³I) (methyl(1R,2S,3S,5S)-3-(4-iodophenyl)-8-(3-fluoropropyl)-8-azabicyclo[3.2.1]octane-2-carboxylate);Nocaine (methyl(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate);Tesofensine((1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane);Troparil (methyl(1R,2S,3S,5S)-8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-2-carboxylate);Tropoxane (methyl(1R,2S,3S,5S)-3-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]octane-2-carboxylate);(+Methyl-1-methyl-4β-(2-naphthyppiperidine-3β-carboxylate (methyl(3S,4S)-1-methyl-4-naphthalen-2-ylpiperidine-3-carboxylate); PIT(2-Propanoyl-3-(4-isopropylphenyl)-tropane); PTT(2β-Propanoyl-3β-(4-tolyl)-tropane); RTI-121, IPCIT (propan-2-yl(1R,2S,3S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate);RTI-126((1R,2S,3S,5S)-8-methyl-2-(1,2,4-oxadiazol-5-methyl)-3-phenyl-8-azabicyclo[3.2.1]octane);RTI-150 (cyclobutyl(1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate);RTI-336((1R,2S,3S,5S)-8-methyl-2-(3-(4-methylphenyl)isoxazol-5-yl)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octane);WF-23 (2β-Propanoyl-3β-(2-naphthyl)-tropane); WF-33(2α-(Propanoyl)-3β-(2-(6-methoxynaphthyl))-tropane).

The medical fluid according to embodiments may be used for any organ,tissue or parts thereof and will have beneficial effects, for examplereduced edema formation.

In particular, the heart will benefit by the medical fluid, which inaddition seems to decrease cardiac irritability.

In addition, it has been found that pulmonary edema may decrease by theuse of the medical fluid, which will improve the result of subsequentpulmonary transplantation.

The same is true for other organs, such as kidney, liver, pancreas,small bowels, intestines, etc. This may be explained by the improvedvasotonus obtained.

The medical fluid may in addition to cocaine or a stimulating analoguethereof, adrenaline and/or noradrenaline, further contain additionalcomponents such as at least one of: an oncotic agent, such as dextran;hormones, such as thyroxin (T4), triiodotyronine (T3), cortisone;electrolytes and optionally nutrients in substantially physiologicalconcentrations in a physiologically acceptable medium; albumin; and anoxygen carrier, such as erythrocytes; further hormones or substances,such as insulin; dopamine; hydrocortisone; methylprednisolone; and avasopressor agent, such as desmopressin, or Minirin.

The oncotic agent may be Dextran 40 in a concentration of 0% to 6.0%.Albumin also acts as an oncotic agent and if albumin is present, Dextran40 may be reduced or eliminated. If no albumin is present, theconcentration of Dextran 40 should be in the higher range. Albumin maybe replaced by recombinant serum albumin or bovine serum albumin.Dextran 40 may be partly or entirely replace by Dextran 70 or anotherDextran compound and/or derivatives thereof.

The ratio between the cocain:adrenaline:nor-adrenaline may be about1:1:1.

In some embodiments, the adrenaline and/or nor-adrenaline may be partlyor entirely replaced by an equivalent substance. For example,phenylephrine is an alfa-1-agonist and may replace nor-adrenaline. Itseems that phenylephrine is about 5 times less potent as nor-adrenaline.

Erythrocytes may be replaced by synthetic oxygen carriers.

Dopamine may be added in quantities corresponding to an infusion of lessthan about 0.01 mg/kg/min.

Hormones should be added as required. It has been found that the levelsof the hormones thyroxin (T4), triiodotyronine (T3), and cortisone arereduced rapidly in the harvested organ, and may be replaced and includedin the medical fluid. Further hormones may be added as needed, such asinsulin. Vasopressin may also be rapidly reduced in the harvested organand may be included in the medical fluid, for example Desmopressin orMinirin.

Electrolytes and optionally nutrients are included in the medical fluid.Electrolytes are for example those included in Kreb's solution.Nutrients may be physiologically acceptable carbohydrates, such asglucose, fatty acids and amino acids or any combinations thereof.

Further substances may be added, such as antibiotics.

In one embodiment, the medical fluid comprises cocaine or a stimulatinganalogue, and in addition adrenaline, nor-adrenaline, cortisone,thyroxin, triiodotyronine, desmopressin, electrolytes and albumin.Erythrocytes are added before use.

The embodiments also relate to a medical fluid comprising thecomposition as defined above dissolved in a pharmaceutical acceptablemedium. Examples of acceptable mediums are physiological sodium chloridesolution, Hartmann's solution and Ringer's (acetate) solution orsterile, non-ionic water, i.e. pure H₂O.

One embodiment of the medical fluid may have the following composition:

1) The basis is a Kreb's solution, comprising for example NaCl, 110-135mM; NaHCO₃, 15-35 mM; KCl, 2.5-4.6 mM; MgCl₂, 1.0-2.6 mM; CaCl₂,1.5-2.4; NaH₂PO₄, 1.0-2.0 mM; Glucose 1-15%, such as about 10%. KCl maybe 15-25 mM or as high as 125 mM if a cardioplegic fluid is required.

2) Albumin, between 2.0% and 5.5%, such as 5.0%, or between 2.0% and4.5%, such as 4.0%,

3) Dextran 40, between 0% and 5.0%, such as 0.5%

4) Cocaine and adrenaline and noradrenaline, each about 0.001 to 0.1 μM,such as 0.01 μM. In another embodiment, cocaine and nor-adrenaline areincluded in the mentioned concentrations. In a further embodiment,cocaine and adrenaline are included in the mentioned concentrations.

5) T3/T4, vasopressin and cortisone, each 0.1 μM

6) Erythrocytes to a hematocrit of 0% to 25%, such as 15%

Erythrocytes may be replaced by synthetic oxygen carriers.

Dextran 40 may be partly or entirely replace by Dextran 70 or anotherDextran compound and/or derivatives thereof.

When the organ has been evaluated by any known method and using themedical fluid, the organ may be preserved awaiting transplantation. Suchpreservation often takes place in a hypothermic condition, such as atemperature below 20° C., for example below 15° C., such as about 10° C.During hypothermic conditions, the metabolism of the cells of the organis reduced.

Thus, a preservation fluid may not require all components of the medicalfluid.

One embodiment of the medical fluid may have the same composition as theabove-mentioned fluid, except:

2) No albumin is required.

3) Dextran 40, between 1% and 5.0%, such as 4%

6) No erythrocytes are required.

Because the preservation fluid does not comprise albumin anderythrocytes, it is less expensive, but will still maintain the organ ina good condition for subsequent transplantation. The Dextranconcentration will be sufficient for maintaining an oncotic pressure,which will prevent edema formation, in addition tococaine/adrenaline/nor-adrenaline.

The medical fluid may be provided without erythrocytes, which are addedshortly before use.

The medical fluid may be provided without an oncotic agent, which isadded shortly before use, such as a combination of albumin and Dextran40.

Thus, a medical fluid may be provided, which is suitable forpreservation. If the solution should be used for evaluation, certainadditions are made before use, such as addition of albumin, Dextran 40and erythrocytes.

The evaluation and preservation may take place by arranging the organ ina device, such as the device disclosed in WO2009136838A1, the contentsof which are incorporated in the present specification by reference.

The organ may be partly or completely immersed in the fluid. In additionor alternatively, the fluid may be introduced into the vascular systemof the organ and be circulated there through.

Since the evaluation may take place at a physiological temperature,hormones and other substances may be consumed, and need to be replacedintermittent or continuously to maintain the concentration thereof.During hypothermic preservation, replacement may not be required.

During preservation, the circulation may not be required, but thepreservation fluid may be present inside the vascular system. Inaddition or alternatively, the organ may be partly or completelyimmersed in the preservation fluid.

Instead of immersing the organ in the second fluid, the fluid may bearranged to drip onto the organ, which is surrounded by cloths, so thatthe organ is kept moist. In addition, the organ may be arranged in amoist atmosphere.

There is no strict distinction between a preservation fluid and anevaluation fluid. Thus, the same medical fluid may be used forevaluation and preservation purposes.

Another alternative option is to use a more versatile first medicalfluid inside the vascular system and a less versatile second medicalfluid outside the organ, which is partly or completely immersed in thesecond fluid. In this case the first fluid may comprise erythrocytesand/or albumin, while the second fluid may lack erythrocytes and/oralbumin.

In addition, the evaluation at the same time comprises preservation,since the evaluation takes some time during which the organ needs to bepreserved.

As mentioned above, there are indications in the literature that anor-adrenaline plasma concentration in the living body of about 1.5 mgper liter (about 9 μM) is required in order to observe a physiologicalchange. Furthermore, the addition of nor-adrenaline in suchconcentration has been reported to have adverse effects. Thus, additionof nor-adrenaline in a concentration below 0.1 μM should be expected tohave substantially no effect. However, the inclusion of cocaine seems topotentiate the effect of nor-adrenaline so that a favorable effect isobtained, without causing adverse effects. Without being bound by anytheory, the above explanation may be valid.

The corresponding plasma concentration for adrenaline is about 0.05 mgper liter (0.3 μM). Also for adrenaline, the cocaine seems to have apotentiating effect so that low concentrations of adrenaline stillresults in a favorable effect.

In the claims, the term “comprises/comprising” does not exclude thepresence of other elements or steps. Furthermore, although individuallylisted, a plurality of means, elements or method steps may beimplemented by e.g. a single unit. Additionally, although individualfeatures may be included in different claims or embodiments, these maypossibly advantageously be combined, and the inclusion in differentclaims does not imply that a combination of features is not feasibleand/or advantageous. In addition, singular references do not exclude aplurality. The terms “a”, “an”, “first”, “second” etc. do not preclude aplurality. Reference signs in the claims are provided merely as aclarifying example and shall not be construed as limiting the scope ofthe claims in any way.

Although the present invention has been described above with referenceto specific embodiment and experiments, it is not intended to be limitedto the specific form set forth herein. Rather, the invention is limitedonly by the accompanying claims and, other embodiments than thosespecified above are equally possible within the scope of these appendedclaims.

1. A medical fluid for a harvested organ, tissue or parts thereof, forevaluation and/or preservation, comprising: cocaine or a stimulatinganalogue thereof; adrenalin and/or noradrenalin; an oncotic agent;hormones; and electrolytes and optionally nutrients in substantiallyphysiological concentrations in a physiologically acceptable medium. 2.The fluid according to claim 1, in which noradrenaline is present in aconcentration of about 0.010 μM to 0.100 μM.
 3. The fluid according toclaim 1, in which adrenaline is present in a concentration of about0.010 μM to 0.100 μM.
 4. The fluid according to claim 1, in whichcocaine or a stimulating analogue thereof is present in a concentrationof about 0.010 μM to 0.100 μM.
 5. The fluid according to claim 1,wherein said oncotic agent is albumin or dextran or a combinationthereof.
 6. The fluid according to claim 1, wherein said hormones areany one of thyroxin; triiodotyronine; or cortisone or a combinationthereof.
 7. The fluid according to claim 1, further comprising an oxygencarrier, such as erythrocytes.
 8. The fluid according to claim 1,further comprising at least one of glucose; insulin; dopamine;hydrocortisone; methylprednisolone; and a vasopressor agent, such asdesmopressin.
 9. The fluid according to claim 1, wherein cocaine or astimulating analogue thereof; adrenalin; and noradrenaline are presentin concentrations of each about 0.010 μM to 0.100 μM.
 10. The fluidaccording to claim 1, wherein cocaine or a stimulating analogue thereof;adrenalin; and noradrenaline are present in concentration ratios of1:1:1.
 11. A method for treatment of a harvested organ for evaluationand/or preservation, comprising: circulating a first fluid in thevascular system of the organ, and optionally partly or completelyimmersing said organ in a second fluid; said first fluid comprisingcocaine or a stimulating analogue thereof; adrenalin and/ornoradrenalin; an oncotic agent; hormones; and electrolytes andoptionally nutrients in substantially physiological concentrations in aphysiologically acceptable medium.
 12. The method according to claim 11,in which noradrenaline is present in a concentration of about 0.010 μMto 0.100 μM.
 13. The method according to claim 11, in which adrenalineis present in a concentration of about 0.010 μM to 0.100 μM.
 14. Themethod according to claim 11, in which cocaine or a stimulating analoguethereof is present in a concentration of about 0.010 μM to 0.100 μM. 15.The method according to claim 11, in which said first fluid furthercomprises: at least one of glucose; albumin; insulin; dopamine;hydrocortisone; methylprednisolone; a vasopressor agent; and an oxygencarrier.
 16. The method according to claim 11, in which said secondfluid further comprises: at least one of glucose; albumin; insulin;dopamine; hydrocortisone; methylprednisolone; and a vasopressor agent,such as desmopressin; and an oxygen carrier, such as erythrocytes. 17.The method according to claim 11, wherein said first fluid is the sameas said second fluid.
 18. Use of a fluid for a harvested organ, tissueor part thereof for evaluation and/or preservation, wherein the fluidcomprises: cocine or a stimulating analogue thereof; adrenalin; and/ornor-adrenalin; an oncotic agent; hormones; triiodotyronine; cortisone;electrolytes and optionally nutrients in substantially physiologicalconcentrations in a physiologically acceptable medium.
 19. The useaccording to claim 18, wherein the fluid further comprises at least oneof: glucose; albumin; insulin; dopamine; hydrocortisone;methylprednisolone; a vasopressor agent; and an oxygen carrier.